Synopses & Reviews
The Cellular Response to the Genotoxic Agent: The Question of Threshold for Genotoxic Carcinogens describes the different cellular defence mechanisms and their regulation. On the basis of this the plausibility of a dose dependent threshold mechanisms of genotoxic/ mutagenic carcinogens and their rate limiting parameters are discussed and it is concluded that low exposures to genotoxic/mutagenic agents present no cancer risk. The book begins with a detailed introduction by the editors explaining the rationale for thresholds for genotoxic carcinogens. The contents are then broken down into five main parts. The first part discusses threshold effects observed in experimental studies and includes chapters on mechanisms responsible for the chromosome and gene mutations driving carcinogenesis and implications for dose-response characteristics of mutagenic carcinogens; the dose-effect relationships of DNA-reactive liver carcinogens and DNA alkylation and repair after EEMS exposure. Part two discusses metabolic inactivation of genotoxic reactants and includes chapters on enzymatic detoxification of endogenously produced DNA-reactive intermediates maintaining cellular homeostasis and detoxifying enzymes and anti-oxygen defense mechanisms. Part three focuses on DNA repair; the plasticity of DNA damage response during cell differentiation and tumor suppressor protein-mediated regulation of base excision repair in response to DNA damage. Finally, the role of apoptosis, necrosis and epigenetic mechanisms in the elimination of damaged cells is discussed. The book will be essential reading for postgraduate students and scientific researchers working in environmental health, medicine, genetic toxicology and risk assessment.
Review
"This book will, therefore, make excellent and stimula ting reading for all toxicologists (from the student to the most senior toxicologist} in academia, industry and government as well as scienlists responsible for health risk assessment. It urges readers to accept scientifically based thresholds not only for non-genotoxic (epigenetic) carcinogens but also - and more importantly - for genotoxic carcinogens. It is highly recommended!" Hans Marquardt, Hamburg, Germany
Synopsis
Although the cellular defence mechanisms are increasingly understood, the critical and rate limiting parameters and their dose-response to the insulting agent need to be evaluated. In this book the different cellular defence mechanisms and their regulation are described. Understanding the protective mechanisms by which the cell responds to a genotoxic impact to protect integrity of the genomes will permit the evaluation of whether the assumption of a threshold for genotoxic carcinogens at low dose exposure is justified. Besides its scientific value, this dispute is of regulatory importance since it may result in a scientifically defendable threshold concept for genotoxic carcinogens, will allow identification of a NOEL and by that to propose health based exposure limits - even for genotoxic carcinogens.
Synopsis
This book considers the exposure levels at which genotoxins pose a risk and describes the cellular mechanisms used against them.
Synopsis
Genotoxic carcinogens can lead to DNA mutations with the potential to cause cancer. Typically, a series of mutation events are needed before malignancy occurs so a single, small exposure may not result in disease. Also, cells have an armoury of defence mechanisms which, to a degree, counter the effects of mutagens. Distinguishing the point at which exposure to a carcinogen increases mutation rates beyond the background level is challenging. In fact, there is now general agreement that, for genotoxic carcinogens, no specific threshold can be identified. However, NOAELs (No Observed Adverse Effect Levels) may be used in the process of establishing a dose-response relationship. These denote the level of exposure at which there is no significant increase in adverse effects in the exposed population when compared to an appropriate control. Such a scientifically defendable threshold allows us to propose health based exposure limits for genotoxic carcinogens. This book describes the various cellular defence mechanisms individually and explains how they are regulated. The processes covered include metabolic inactivation, epigenetic regulation, scavenging mechanisms, DNA-repair and apoptosis. It also considers dose-dependent threshold mechanisms of carcinogenesis and the rate limiting parameters. Aimed at graduate level and above, the book discusses the consequences of genotoxic evaluation and urges readers to question the idea that even low exposures present a cancer risk.
Synopsis
So far, there is general agreement that for genotoxic carcinogens no threshold can be identified. However, there are examples that the shape of the dose-responses of DNA adducts and mutations differ and it is also evident that the dose response for mutations will reach the background mutation frequency. This implies, that at low doses the mutation rate induced by a genotoxic/mutagenic carcinogen becomes indistinguishable from the background. Moreover, the array of cellular defence mechanisms such as metabolic inactivation, DNA-repair and apoptosis makes it unlikely that a single event overcomes these barriers to cancer. This confirms the experimental evidence of NOELs for carcinogenic and mutagenic effects in repeated dose studies in animals. In this book the different cellular defence mechanisms and their regulation are described. On the basis of this the plausibility of a dose dependent threshold mechanisms of genotoxic/mutagenic carcinogens and their rate limiting parameters are discussed and it is concluded that the notion that even low exposures to genotoxic/mutagenic agents present a cancer risk is to be questioned.
About the Author
Helmut Greim is a toxicologist and former chair of the Institute of Toxicology and Environmental Hygiene at the Technical University of Munich, Germany. His research experience is drug metabolism, toxicokinetics, mechanisms of carcinogenic agents, in vitro test systems. He has been member or chair of numerous national and international scientific committees. In 1996 he received the Arnold Lehman Award of SOT and in 2001 the Herbert Stockinger Award of the American Conference of Governmental Industrial Hygienists. At present he chairs the Scientific Committee on Health and Environmental Risks of the DG SANCO, Brussels, is member of the Scientific Committee on Occupational Exposure Limits of DG EMPLOYMENT, Luxembourg and member of the Risk Assessment Committee of the European Chemicals Agency in Helsinki, Finland. Dr. Albertini is currently Research Professor of Pathology at the University of Vermont (USA). He retired from the Department of Medicine at that University in 2000 and is now an Emeritus Professor of Medicine. He received the M.D. degree in 1963 and a Ph.D. in Medical Genetics in 1972, both from the University of Wisconsin, Madison (USA). Dr. Albertini joined the Department of Medicine at the University of Vermont that same year, becoming full Professor in 1979. He was clinically active in the areas of oncology, hematology and AIDS for many years and served as Director of the Vermont Cancer Center from 1993 to 1995. Dr. Albertini's fundamental research has been and remains in the area of mutagenesis and the relationship of somatic mutations to cancer. In the past, Dr. Albertini served as President of the Environmental Mutagen Society and as editor-in-chief of Environmental and Molecular Mutagenesis.
Table of Contents
Introduction: The rationale for thresholds for genotoxic carcinogens; Part 1. Threshold effects observed in experimental studies: Mechanisms responsible for the chromosome and gene mutations driving carcinogenesis: implications for dose-response characteristics of mutagenic carcinogens; Dose-effect relationships of DANN-reactive liver carcinogens; DNA alkylation and repair after EEMS exposure: Where do the thresholds for mutagenic/clastogenic effects arise? Part 2. Metabolic inactivation of genotoxic reactants: Enzymatic detoxification of endogenously produced mutagenic carcinogens maintaining cellular homeostasis; Phase 2 detoxifying enzymes and anti-oxygen defense mechanisms in the inactivation of genotoxic carcinogens; Part 3. DNA repair: Consequences and Repair of oxidative DNA damage; The plasticity of DNA damage response during cell differentiation: pathways and consequences; Tumor suppressor protein-mediated regulation of base excision repair in response to DNA damage; Part 4. Apoptosis: Survival and death strategies in cells exposed to genotoxin; Different modes of cell death induced by DNA damage; Transcriptional inhibition by DNA damage as a trigger of cell death; Part 5. Epigenetic mechanisms: The interplay between epigenetics and Gap junctionional intercellular communication; Index